Citations

Abstract Brain metabolism perturbation can contribute to traits and diseases. We conducted the first large-scale CSF and brain genome-wide association studies, which identified 219 independent associations (59.8% novel) for 144 CSF metabolites and 36 independent associations (55.6% novel) for 34 brain metabolites. Most of the novel signals (97.7% and 70.0% in CSF and brain) were tissue specific. We also integrated MWAS-FUSION approaches with Mendelian Randomization and colocalization to identify causal metabolites for 27 brain and human wellness phenotypes and identified eight metabolites to be causal for eight traits (11 relationships). Low mannose level was causal to bipolar disorder and as dietary supplement it may provide therapeutic benefits. Low galactosylglycerol level was found causal to Parkinson’s Disease (PD). Our study expanded the knowledge of MQTL in central nervous system, provided insights into human wellness, and successfully demonstrates the utility of combined statistical approaches to inform interventions.

Abstract Over one million biopsies are performed annually in the U.S. to evaluate suspicious breast lesions. Most biopsies lead to a diagnosis of benign breast disease (BBD) and these women have a 1.5- to fourfold increase in subsequent breast cancer (BC) risk compared with the general population. A polygenic risk score (PRS) including 313 common variants was developed to predict BC risk in the general population and has improved performance when added to existing BC prediction models. However, the value of PRS in risk prediction models among women with BBD has not been evaluated. To evaluate the role of the established PRS, BBD, and BC risk, we pooled data from 15,194 white women (6,706 BC cases and 8,488 controls) participating in five Breast Cancer Association Consortium case-control studies. BC risk associations were evaluated by self-reported BBD history and combinations of PRS expressed in tertiles using odds ratios (OR), considering the lowest category of PRS among women without BBD as the referent. Associations were also assessed in an independent case-cohort study (831 BC cases and 1,845 controls) using hazard ratios (HR). Among the case-control studies, the PRS was strongly associated with BC risk (OR=2.50 per standard deviation increase), and associations were similar in women with (OR=2.60) and without a history of BBD (OR=2.44, p-interaction=0.23). Women with BBD have a higher risk of BC than those without BBD within each level of PRS. Compared to women without BBD and in the lowest PRS category, those with BBD and PRS in the highest tertile had 5-fold increased odds of BC (OR = 5.38; 95% CI 4.73-6.13). Associations were similar in an independent case-cohort study. These findings indicate that BBD history and PRS are independent contributors to BC risk, and consideration of both simultaneously could improve breast cancer risk prediction. Future studies are needed to integrate PRS with other risk measures to refine absolute BC risk prediction among BBD patients. Associations of BC risk with combinations of PRS (tertiles) and history of BBD in five case-control studies and a case-cohort study from the Breast Cancer Association Consortium. Case-control studies Case-cohort study PRS score range History of BBD n BC cases n controls OR (95% CI)1 n BC cases n controls HR (95% CI)2 Tertile 1 (≤ -0.57) No 1009 2692 1.00 (Ref) 117 584 1.00 (Ref) Yes 508 902 1.54 (1.35-1.76) 69 163 2.05 (1.45-2.89) Tertile 2 (-0.58, -0.03) No 1469 2001 1.97 (1.78-2.17) 181 475 1.93 (1.48-2.51) Yes 760 798 2.65 (2.34-3.01) 108 170 2.99 (2.18-4.09) Tertile 3 (≥ -0.02) No 1910 1551 3.32 (3.01-3.67) 214 336 3.28 (2.52-4.26) Yes 1050 544 5.38 (4.73-6.13) 142 117 4.83 4.25-8.02) 1.Logistic regression analysis, adjusted for study site/genomic platform and age at enrollment. OR, odds ratio; CI, confidence interval.2.Cox proportional hazards regression analysis, accounting for the case-cohort study design and adjusted for age at enrollment. HR, hazard ratio; CI, confidence interval. Citation Format: Stacey J. Winham, Mark Sherman, Robert Vierkant, Bryan McCauley, Christopher Scott, Mia Gaudet, Melissa Troester, Sandhya Pruthi, Derek Radisky, Amy Degnim, Kristan Aronson, Rachel Murphy, Pascal Guenel, Therese Truong, Jenny Chang-Claude, Heiko Becher, Montserrat Garcia-Closas, Stephen Chanock, Thomas Ahearn, Xiaohong Yang, Doug Easton, Manjeet Bolla, Celine Vachon, Breast Cancer Association Consortium. Association of polygenic risk scores with breast cancer risk among women with benign breast disease. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5241.

AbstractBackgroundDeformable Image Registration (DIR) is an essential technique required in many applications of radiation oncology. However, conventional DIR approaches typically take several minutes to register one pair of 3D CT images and the resulting deformable vector fields (DVFs) are only specific to the pair of images used, making it less appealing for clinical application.PurposeA deep‐learning‐based DIR method using CT images is proposed for lung cancer patients to address the common drawbacks of the conventional DIR approaches and in turn can accelerate the speed of related applications, such as contour propagation, dose deformation, adaptive radiotherapy (ART), etc.MethodsA deep neural network based on VoxelMorph was developed to generate DVFs using CT images collected from 114 lung cancer patients. Two models were trained with the weighted mean absolute error (wMAE) loss and structural similarity index matrix (SSIM) loss (optional) (i.e., the MAE model and the M+S model). In total, 192 pairs of initial CT (iCT) and verification CT (vCT) were included as a training dataset and the other independent 10 pairs of CTs were included as a testing dataset. The vCTs usually were taken 2 weeks after the iCTs. The synthetic CTs (sCTs) were generated by warping the vCTs according to the DVFs generated by the pre‐trained model. The image quality of the synthetic CTs was evaluated by measuring the similarity between the iCTs and the sCTs generated by the proposed methods and the conventional DIR approaches, respectively. Per‐voxel absolute CT‐number‐difference volume histogram (CDVH) and MAE were used as the evaluation metrics. The time to generate the sCTs was also recorded and compared quantitatively. Contours were propagated using the derived DVFs and evaluated with SSIM. Forward dose calculations were done on the sCTs and the corresponding iCTs. Dose volume histograms (DVHs) were generated based on dose distributions on both iCTs and sCTs generated by two models, respectively. The clinically relevant DVH indices were derived for comparison. The resulted dose distributions were also compared using 3D Gamma analysis with thresholds of 3 mm/3%/10% and 2 mm/2%/10%, respectively.ResultsThe two models (wMAE and M+S) achieved a speed of 263.7±163 / 265.8±190 ms and a MAE of 13.15±3.8 / 17.52±5.8 HU for the testing dataset, respectively. The average SSIM scores of 0.987±0.006 and 0.988±0.004 were achieved by the two proposed models, respectively. For both models, CDVH of a typical patient showed that less than 5% of the voxels had a per‐voxel absolute CT‐number‐difference larger than 55 HU. The dose distribution calculated based on a typical sCT showed differences of ≤2cGy[RBE] for clinical target volume (CTV) D95 and D5, within ±0.06% for total lung V5, ≤1.5cGy[RBE] for heart and esophagus Dmean, and ≤6cGy[RBE] for cord Dmax compared to the dose distribution calculated based on the iCT. The good average 3D Gamma passing rates (> 96% for 3 mm/3%/10% and > 94% for 2 mm/2%/10%, respectively) were also observed.ConclusionA deep neural network‐based DIR approach was proposed and has been shown to be reasonably accurate and efficient to register the initial CTs and verification CTs in lung cancer.

AbstractBackgroundAbsolute dosimetry measurement is an integral part of Treatment Planning System (TPS) commissioning and it involves measuring the integrated absorbed dose to water for all energies in a pencil beam scanning delivery system. During the commissioning of Singapore's first proton therapy center, a uniform scanned field with an Advanced Markus chamber method was employed for this measurement, and a large dose fluctuation of at least 5% was observed for 10% of the energy layers during repeated measurements.PurposeThis study aims to understand the root cause of this fluctuation by relating the actual delivered spot information in the log file with the charge measurement by the ion chambers.MethodsA dedicated pencil beam dose algorithm was developed, taking into account the log file parameters, to calculate the dose for a single energy layer in a homogeneous water phantom. Three energies, 70.2, 182.7, and 228.7 MeV were used in this study, with the 182.7 MeV energy exhibiting large dose fluctuation. The dose fluctuation was investigated as a function of detector's sizes (pinpoint 3D, Advanced Markus, PTW 34070, and PTW 34089) and water depth (2 , 6, and 20 cm). Twelve ion chambers measurements were performed for each chamber and depth. The comparison of the theoretically predicted integrated dose and the charge measurement served as a validation of the algorithm.ResultsAbout 5.9% and 9.6% dose fluctuation were observed in Advanced Markus and pinpoint 3D measurements at 2 cm depth for 182.7 MeV, while fluctuation of 1.6% and 1.1% were observed in Advanced Markus with 228.7 and 70.2 MeV at similar depth. Fluctuation of less than 0.1% was observed for PTW34070 and PTW 34089 for all energies. The fluctuation was found to diminish with larger spot size at 20 cm depth to 1.3% for 182.7 MeV. The theoretical and measured charge comparison showed a high linear correlation of for all datasets, indicating the fluctuation originated from the delivered spot characteristics. The cause of fluctuation was identified to be due to the spill change occurring close to the detector, and since the spot positional deviation profiles were different between two spills, this resulted in local hot spots between columns of spots. The actual position of spill change varies randomly during measurement, which led to a random occurrence of hot spot within the detector's sensitive volume and a fluctuating dose measurement.ConclusionThis is the first report of a dose fluctuation greater than 5% in absolute dosimetry measurement with a uniform scanned field and the cause of the fluctuation has been conclusively determined. It is important to choose the MU and scanning pattern carefully to avoid spill change happening when the spot delivery is near the detector.

AbstractBackgroundIt is challenging to assess the accuracy of volume CT Dose Index (CTDIvol) when the axial scan modes corresponding to a helical scan protocol are not available. An alternative approach was proposed to directly measure using helical acquisitions and relatively small differences (< 20%) from CTDIvol were observed.PurposeTo visually demonstrate the 3D dose distribution for both axial and helical CT acquisitions and quantitively compare and CTDIvol.Methods3D dose distribution within the standard CTDI phantoms (16 and 32 cm diameter) from a single CT projection, Dp(x,y,z) was first generated using Monte Carlo simulation (GEANT4) with 9×108 photons per combination of tube voltage (80–140 kV), collimation width (1–8 cm), and z‐axis location of the central ray of the x‐ray beam, with a spatial resolution of 1 mm3. These dose distributions from one single projection were analytically ensembled to simulate 3D dose volumes DA(x,y,z) and DH(x,y,z) for axial and helical scans, respectively, with different helical pitches (0.3–2) and scan lengths (100–150 mm). 2D planar dose distributions were obtained by integrating the inside 100 mm of the dose volumes. CTDIvol and were calculated using the planar dose data at corresponding pencil chamber locations and the percentage differences (PD) were reported.ResultsHigh spatial resolution 3D CT dose volumes were generated and visualized. PDs between and CTDIvol had strong dependency on scan length and peripheral chamber locations, with subtle dependency on collimation width and pitch. PDs were mostly within the range of ± 3% for a scan length of 150 mm with four peripheral chamber locations.ConclusionsWith a scan length covering the entire phantom length, directly measured from helical scans can serve as an alternative to CTDIvol only if all four peripheral locations were measured.

Abstract Purpose: Non-invasive monitoring of circulating tumor DNA (ctDNA) has the potential to be a readily available measure for early prediction of clinical response. Here, we report on early ctDNA changes of KRAS G12C in a Phase 2 trial of adagrasib in patients with advanced, KRAS G12C-mutant lung cancer. Experimental Design: We performed serial droplet digital PCR (ddPCR) and plasma NGS on 60 KRAS G12C-mutant patients with lung cancer that participated in cohort A of the KRYSTAL-1 clinical trial. We analyzed the change in ctDNA at 2 specific intervals: Between cycles 1 and 2 and at cycle 4. Changes in ctDNA were compared with clinical and radiographic response. Results: We found that, in general, a maximal response in KRAS G12C ctDNA levels could be observed during the initial approximately 3-week treatment period, well before the first scan at approximately 6 weeks. 35 patients (89.7%) exhibited a decrease in KRAS G12C cfDNA &gt;90% and 33 patients (84.6%) achieved complete clearance by cycle 2. Patients with complete ctDNA clearance at cycle 2 showed an improved objective response rate (ORR) compared with patients with incomplete ctDNA clearance (60.6% vs. 33.3%). Furthermore, complete ctDNA clearance at cycle 4 was associated with an improved overall survival (14.7 vs. 5.4 months) and progression-free survival (HR, 0.3). Conclusions: These results support using early plasma response of KRAS G12C assessed at approximately 3 weeks to anticipate the likelihood of a favorable objective clinical response.

9004 Background: Despite advances in first-line (1L) immunotherapy ± CT, most patients (pts) with aNSCLC experience disease progression, necessitating novel strategies. Dato-DXd is an antibody drug conjugate (ADC) composed of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a topoisomerase I inhibitor payload via a plasma-stable tetrapeptide-based cleavable linker. Dato-DXd had encouraging efficacy and manageable safety in heavily pretreated aNSCLC. Dato-DXd + immunotherapy yielded greater preclinical activity than either agent alone. Methods: TROPION-Lung02 (NCT04526691) is a phase 1b, global, dose-escalation and -expansion study evaluating Dato-DXd (4 or 6 mg/kg) + pembro 200 mg ± Pt-CT (cisplatin 75 mg/m2 or carboplatin AUC 5) every 21 days across 6 cohorts. Pts in escalation may have received ≤2 prior lines of therapy for aNSCLC. Pts in expansion were primarily treatment (tx) naive (pts receiving Dato-DXd + pembro may have ≤1 prior Pt-based tx). The primary objective is to assess safety and tolerability, including dose-limiting toxicities (DLTs). Secondary objectives include evaluation of efficacy, pharmacokinetics, and immunogenicity. Results: As of the Oct 31, 2022, data cutoff (DCO), 120 pts were treated. All cohorts met DLT criteria to move to escalation. Median age was 65 years. PD-L1 expression was <1%, 1%-49%, and ≥50% in 40%, 33%, and 26% of pts, respectively. Median tx duration was 4.6 mo, with 55% receiving tx at DCO. The most frequent any-grade (gr) tx-emergent adverse events (TEAEs) were nausea (45%) and stomatitis (45%). Gr ≥3 TEAEs occurred in 61% of pts; most frequent were neutrophil count decreased (8%) and amylase increased (8%). TEAEs that were serious, associated with discontinuation, or associated with death occurred in 31%, 24% (16% associated with Dato-DXd), and 6% of pts, respectively. Dose reductions due to TEAEs associated with Dato-DXd occurred in 17%. Drug-related interstitial lung disease occurred in 12 pts (10%; 9 gr 1/2; 3 gr 3). The objective response rate (ORR) with 1L Dato-DXd + pembro doublet and Dato-DXd + pembro + Pt-CT triplet tx was 60% (95% CI, 36%-81%; 12 [2 unconfirmed]/20) and 55% (95% CI, 39%-70%; 23 [5 unconfirmed]/42), respectively. The ORR for any line of therapy was 38% (95% CI, 25%-54%; 18 [2 unconfirmed]/47) with doublet and 47% (95% CI, 34%-60%; 28 [5 unconfirmed]/60) with triplet tx. In both subsets, the disease control rate was 85% and median duration of response was not reached. Responses were observed in all 3 PD-L1 expression level subgroups. Although immature, median progression-free survival (95% CI) was 10.8 (8.3-15.2) and 7.8 mo (5.5-NE) with doublet and triplet tx, respectively. Conclusions: Dato-DXd + pembro ± Pt-CT demonstrated tolerable safety with notable 1L activity in this first and largest dataset with an ADC + immunotherapy ± Pt-CT in aNSCLC pts. Clinical trial information: NCT04526691 .

e19530 Background: In large B-cell lymphoma (LBCL) trials, racial and ethnic representation is difficult to determine due to underreporting in some regions, or because some patients may not provide data. It is difficult to understand the full extent of any underrepresentation of specific races or ethnicities in these trials relative to the prevalence of LBCL in clinical practice. The objective of this study was to characterize racial and ethnic representation in LBCL real-world databases and recently published LBCL studies. Methods: Analyses of the distribution of different racial and ethnic categories were conducted across 6 real-world clinical practice databases from the United States (US): SEER-Medicare, COTA, Medicare, Optum Market Clarity, Optum CDM, and ConcertAI RWD. In addition, a targeted review of recently published studies in patients with LBCL was conducted to identify reported race and ethnicity distributions. Distributions were described using counts and percentages for each race (Asian, Black, White, and other/unknown/not reported) and ethnicity (Hispanic, non-Hispanic, and other/unknown/not reported) category. Results: Patients with LBCL from the databases included: COTA (N=5848), SEER-Medicare (N=102,548), Medicare (N=136,466), Optum Market Clarity (N=19,649), Optum CDM (N=22,175), and ConcertAI (N=1828). Race and ethnicity distributions are reported in the table. Across databases, Asian (2–6%) and Black (5–8%) races were substantially lower than White race (69–88%). Across various lines of therapy, distributions were similar: 3–5% Asian, 3–5% Black, and 78–82% White. Hispanic ethnicity (5–22%) was substantially lower than non-Hispanic ethnicity (70–91%). In the targeted review, 14 publications of LBCL therapies were identified; of these, 10 did not report racial/ethnic composition. In 4 publications (Salles et al, 2020; Sehn et al, 2020; Bannerji et al, 2022; and a real-world study by Shenoy et al, 2011), Asian, Black, White, and other/unknown/not reported represented 2–13%, 0–7%, 71–89%, and 1–11%, respectively. Conclusions: Information on racial and ethnic distributions in LBCL studies is underreported, particularly in global trials. If this information was reported and reflective of LBCL in clinical practice in the US, the numbers of Asian and Black patients would be low at ≤8%, and most patients would be expected to be White and non-Hispanic. [Table: see text]

5094 Background: In prior studies, basal vs. luminal differentiation portends differential response to a) androgen suppression (AS) duration for high-risk prostate cancer (PCa) (NRG-GU-TS006) and b) docetaxel chemotherapy (CT) and AS for metastatic hormone-sensitive disease (CHAARTED). In NRG-GU-TS006, basal tumors appeared to benefit the most from longer duration of AS while those with luminal subtype did not whereas, in CHAARTED, luminal subtype had greater benefit from addition of CT. Herein, we examined basal-luminal subtyping to predict differential response to the addition of CT in the setting of high-risk PCa treated with AS and definitive radiotherapy (AS + RT) in NRG/RTOG 0521. Methods: Per pre-specified and approved NCI analysis plan (Navigator #1061), we obtained available NRG biobank biopsy specimens from patients enrolled on the NRG/RTOG 0521 phase III trial, which randomized patients to AS + RT +/- CT. The highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays (Veracyte, San Diego, CA). Basal-luminal subtypes were generated using a 215-gene PCa subtyping classifier (PSC), a second generation PAM50 basal-luminal model. Treatment effects in Luminal Proliferating (LP) and non-LP subtypes were examined with Cox (for overall survival, OS, and metastasis-free survival, MFS) and Fine & Gray (for distant metastasis, DM) multivariable (MVA) models adjusted for age and trial risk stratification, as well as with restricted mean survival times (RMST). Results: Of 183 samples available for analysis (91 from control and 92 from the CT arm), 52 (28%) were classified as LP subtype. Median follow-up for OS was 9.9 years. No significant differences in clinical or pathological variables were observed between LP and non-LP subtypes. In MVA, we did not detect any significant LP subtype-by-CT treatment interaction but observed evidence of non-proportional hazards (Grambsch-Therneau test, p<0.05). In unselected patients, 5- and 10-year RMST difference between the arms was 0.9 (95% CI [-1.5, 3.4], p=0.46) and 5.7 (95% CI [-2.5, 13.9], p=0.17) months of OS. Stratifying by tumor subtype, at 5 years the RMST difference in months was 3.8 (95% CI [0.3, 7.2], p=0.03) for LP and -0.2 ([-3.4, 2.9], p=0.89) for non-LP. The RMST difference in months at 10-years was 13.7 (95% CI [-0.2, 27.5], p=0.053) for LP and 2.5 ([-7.6, 12.5], p=0.63) for non-LP. Conclusions: In pre-treatment biopsy samples from a Phase 3 trial cohort of localized high-risk men, luminal-basal subtyping of tumors demonstrated differential response to docetaxel CT. Similar to results from the CHAARTED trial of metastatic disease, LP tumors may derive greater benefit from addition of CT. Validation of these findings may enable effective earlier use of CT in men with PCa.